This application is based on the observation that hypoxemia is a precipitatory factor in the etiology of sudden infant death syndrome (SIDS), and that maternal smoking is a major risk factor. Linking these observations, we have shown that nicotine blunts the ventilatory response to hypoxia in young lambs. Therefore, the objective of this application is to determine through what mechanisms postnatal nicotine exposure affects the development of responsiveness to hypoxia. Unsedated, chronically instrumented lambs will be studied serially for four weeks after birth with a new technique which allows breath-by-breath measurements of ventilation and occlusion pressures, an index of central respiratory drive. Special emphasis will be placed on the study of clinically relevant respiratory compensatory mechanisms, such as the ventilatory response to alveolar hypoxia, to apnea reflex stimulation, and to inspiratory resistance. Dopamine (DA) acts as an inhibitory neuromodulator both in the carotid body (CB) and in the respiratory related nuclei in the brainstem. Nicotine facilitates DA release from dopaminergic neurons in various areas of the central nervous system. Therefore, the following hypotheses will be tested: 1) the inhibitory effect of nicotine on responsiveness to hypoxia is due to a combined dopaminergic inhibition of the peripheral chemoreceptor and the central integration of their afferent input. The following measurements will be performed to determine whether the depressive effect of nicotine on responsiveness to hypoxia is mediated through an increased DA release in the carotid body: 1)levels of mRNA coding for the catecholamine synthesizing enzyme tyrosine hydroxylase in CB; 2) content of dopamine and dopamine metabolites in CB; 3) response to hypoxia after peripheral dopamine D2-receptor blockade. To determine whether the nicotine effect is mediated by a central influence of dopamine the following measurements will be performed: 1) DA immunoreactivity in nucleus trachus sollitarii, a relay station for CB afferent input; and 2) response to hypoxia after central dopamine D1-receptor blockade. SIDS is the leading cause of death in infants from 1 month to 12 months of age. Maternal smoking is estimated to account for 30% of all SIDS cases. This study, if successful will demonstrate better the inhibitory effects of maternal smoking on clinically relevant respiratory compensatory mechanism during hypoxia and determine the mechanisms by which this influence is caused.